Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties.
Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties.
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取代的 7,12-二氢吡啶并[3,2-b:5,4-b]二吲哚的合成：具有反向激动剂/拮抗剂特性的刚性平面苯二氮卓受体配体。
DOI：
10.1021/jm00171a015
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发表时间：
1990
影响因子：
7.3
通讯作者：
Cook,JM
中科院分区：
文献类型：
--
作者：
Trudell,ML;Lifer,SL;Tan,YC;Martin,MJ;Deng,L;Skolnick,P;Cook,JM
合成了一系列1-、2-、3-、4-、5-、6-、7-、10-和12-取代的吡啶并二吲哚，并在体外筛选了其对苯二氮卓受体（BzR）的活性。在体外，发现2-取代的吡啶并二吲哚是这类新的BzR配体中最有效的（< 10 nM）。在体内，发现2-甲氧基吡啶并二吲哚19 a（IC 50 = 8 nM）是该系列中最有效的部分反向激动剂（促惊厥剂）。母体化合物2（IC 50 = 4 nM）的效力仅略低。此外，发现2-羟基吡啶并二吲哚21 a（IC 50 = 6 nM）在作为前药衍生物新戊酰酯22给药时表现出有效的促惊厥活性。2-Chloropyridodiindole 16 a（IC 50 = 10 nM）没有促惊厥活性;然而，发现16 a是这类BzR配体中地西泮抗惊厥作用的最有效拮抗剂。从可用的体内数据来看，用吸电子基团取代2的环E导致BzR处的拮抗剂，而用释放电子基团取代C-2处的氢提供增强的反向激动剂活性。吡啶并二吲哚被用作“模板”的反激动剂/拮抗剂活性位点的theBzR的模型的制定。所提出的模型由氢键受体位点（A1）和氢键供体位点（D2）组成。0-8.5 A的受体蛋白。据信氢键位点位于狭窄裂缝的底部。一个大的亲脂性口袋的口狭窄的裂缝用于直接进入结合位点的分子，而一个小的亲脂性口袋的存在允许取代仅在位置2的吡啶并二吲哚核的最大结合效力。
A series of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 10-, and 12-substituted pyridodiindoles were synthesized and screened in vitro against [3H] diazepam for activity at the benzodiazepine receptor (BzR). In vitro, the 2-substituted pyridodiindoles were found to be the most potent (< 10 nM) of this new class of BzR ligands. In vivo, 2-methoxypyridodiindole 19a (ICso= 8 nM) was found to be the most potent partial inverse agonist (proconvulsant) of the series. The parent compound 2 (IC50= 4 nM) was only slightly less potent. In addition, 2-hydroxypyridodiindole 21a (IC^= 6 nM) was found to exhibit potent proconvulsant activity when administered as a prodrug derivative, pivaloyl ester 22. 2-Chloropyridodiindole 16a (IC50= 10 nM) was devoid of proconvulsant activity; however, 16a was found to be the most potent antagonist of the anticonvulsant effects of diazepam in this class of BzRligands. From the in vivo data available, substitution on ring E of 2 with electron-withdrawing groups results in antagonists at BzR, while replacement of hydrogen at C-2 with electron-releasing groups provides enhanced inverse agonist activity. The pyridodiindoles were used as “templates” for the formulation of a model of the inverse agonist/antagonist active site of theBzR. The proposed model consists of a hydrogen bond acceptor site (A1) and a hydrogen bond donor site (D2) disposed6. 0-8.5 A from each other on the receptor protein. The hydrogen-bonding sites are believed to be located at the base of a narrow cleft. A large lipophilic pocket at the mouth of the narrow cleft serves to direct molecules into the binding site, while the presence of a small lipophilic pocket permits substitution only at position 2 of the pyridodiindole nucleus for maximum binding potency.